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Objectives: To elucidate the mechanism of action of the α 1 -blocker, naftopidil, in partial bladder outlet obstruction animals, by studying non-voiding contractions, and the levels of mediators were measured with resiniferatoxin treatment., Methods: A total of 35 female Wistar rats were randomly divided into a sham or bladder outlet obstruction group, and rats in each group were given vehicle or resiniferatoxin. Incomplete urethral ligation was applied to the bladder outlet obstruction group. After cystometry, the intravesical level of prostaglandin E 2 and adenosine 5'-triphosphate was measured in the instilled perfusate collected. Naftopidil was given at the time of cystometry., Results: In bladder outlet obstruction rats, non-voiding contractions, bladder capacity, and the intravesical levels of prostaglandin E 2 and adenosine 5'-triphosphate were markedly increased compared with sham rats. Naftopidil decreased non-voiding contractions, enlarged the bladder capacity, and decreased the intravesical levels of prostaglandin E 2 and adenosine 5'-triphosphate. Resiniferatoxin enhanced non-voiding contractions. The effects of naftopidil on non-voiding contractions and the intravesical level of prostaglandin E 2 , but not adenosine 5'-triphosphate, were tolerant to resiniferatoxin., Conclusions: In bladder outlet obstruction rats, one cause of generation of non-voiding contractions might be bladder wall distension, but not transient receptor potential cation channel V1. The increase in intravesical prostaglandin E 2 might also be associated with the generation of non-voiding contractions. Naftopidil inhibits the increase in non-voiding contractions and decreases the intravesical level of prostaglandin E 2 , which are independent of transient receptor potential cation channel V1., (© 2019 The Japanese Urological Association.)

Stress-related peptide corticotropin-releasing factor (CRF) and CRF-related peptides are distributed in the peripheral viscera such as the bladder. We investigated the contribution of psychological stress (PS) and CRF on bladder function. Male rats received sham stress (SS) or PS using a communication box method for 120 min every day for 7 days. One group of rats received the intraperitoneal CRF-R1 antagonist antalarmin for 7 days during stress exposure. Mean voided volume per micturition was significantly lower in PS rats compared to SS rats, which was antagonized by antalarmin treatment. Increases in plasma and bladder CRF, and mRNA expressions of bladder CRF, CRF-R1, and M2/3 muscarinic receptors, were found in PS rats. CRF did not influence bladder contraction in itself; however, stress increased the response of muscarinic contraction of bladder strips. These changes were antagonized by antalarmin treatment. In conclusion, PS reinforces M3 receptor-mediated contractions via CRF-R1, resulting in bladder storage dysfunction.

Aims: Androgen deprivation therapy has been widely used for the treatment of prostate cancer. While sexual side effects including decreased sexual desire and function are well studied, there are only limited reports about its influences on lower urinary tract symptoms. The aim of this study is to clarify the influences of castration in male rats., Methods: Ten-week-old male rats were divided into treatment group (bilateral orchiectomy) and control group (sham surgery). Two-months after the surgery, adenosine triphosphate (ATP), prostaglandin E2 (PGE2), and nerve growth factor (NGF) released from stretched bladder epithelium were measured by luciferin-luciferase assay or ELISA. The mRNA levels of bladder cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were determined by real-time PCR. The protein level of bladder COX-2 was analyzed by western blot analysis. Bio-Plex Pro cytokine assay was performed to quantify the level of proinflammatory cytokine interleukin (IL)-1β in the bladder., Results: The PGE 2 release from stretched bladder epithelium was significantly increased after castration, which increased more than 50% compared with control. On the other hand, those of ATP and NGF were not different from those of the controls. Testosterone replacement restored the PGE 2 increase. Castration significantly increased bladder IL-1β protein level and COX-2 at both mRNA and protein levels, whereas caused no marked changes in the COX-1 mRNA level., Conclusions: These findings suggest that castration induces inflammation in the rat bladder, which causes elevated PGE 2 release from bladder epithelium and may finally contribute to the disruption of bladder storage function., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Bladder urothelial carcinoma (UC) comprises more than 90% of all bladder cancers. Among several UC variants, micropapillary UC (MPUC) is a rare one with high potential for lymphovascular invasion and subsequent lymph node metastasis. Histologically, MPUC is characterized by the presence of small papillary carcinoma cell clusters surrounded by lacunar spaces. Immunohistochemically, the outer circumference of these clusters, that is, the stroma-facing membrane of carcinoma cells, is reportedly almost invariably positive for mucin 1 (MUC1) protein and to a lesser extent for sialyl Lewis X (sLeX) carbohydrates; however, the clinicopathological implications of these expression patterns have not been fully investigated., Materials and Methods: We performed immunohistochemical analysis of MPUC (n = 11) and conventional UC (n = 57) for MUC1 and sLeX to determine whether these factors immunolocalized. Dual immunofluorescence staining was also carried out to assess MUC1 and sLeX colocalization. We also performed Western blot analysis of Chinese hamster ovary cells misexpressing both recombinant epitope-tagged MUC1 and glycosyltransferases enabling sLeX biosynthesis., Results: MPUC samples preferentially exhibited both MUC1 protein and sLeX carbohydrate expression on the stroma-facing membrane of carcinoma cells. Based on univariate analysis, MUC1 expression in that pattern was positively correlated with tumor extension, lymphovascular invasion, lymph node metastasis, disease stage, and relatively poor patient prognosis. A comparable sLeX expression pattern also correlated positively with tumor extension and nodal metastasis. Based on multivariate analysis, localization of MUC1 and sLeX on the stroma-facing side of the membrane was positively correlated with lymph node metastasis., Conclusions: Overall, our immunofluorescence findings as well as immunoprecipitation analyses of Chinese hamster ovary cell transfectants strongly suggest that MUC1 is a potential scaffold protein for sLeX carbohydrates in MPUC. Both MUC1 and sLeX may cooperatively contribute to MPUC histogenesis and clinicopathological characteristics., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: There are some reports that bladder C-fibers are partially involved in detrusor overactivity in patients with brain lesions. We investigated the contribution of bladder C-fiber to decreased bladder capacity in rats with cerebral infarction., Methods: Cerebral infarction was induced under halothane anesthesia by left middle cerebral artery occlusion with 4-0 nylon thread in female Sprague-Dawley rats. Intramural amounts of ATP and prostaglandin E 2 , in vivo and in vitro ATP, NGF, and prostaglandin E 2 release from the distended bladder urothelium, and changes in mRNA expressions of sensor molecules and receptors were monitored 6 h after the occlusion. Cystometry was performed in rats with or without resiniferatoxin pretreatment., Results: Overexpression of sensor molecule, transient receptor potential vanilloid-type channel 1, acid-sensing ion channel 2, purinergic receptors P2X 3 , and M 2 /M 3 muscarinic receptors was found in the bladder. These changes were accompanied by increases in ATP and NGF release from the urothelium. In contrast, when bladder C-fibers were desensitized by resiniferatoxin, no increase in NGF release from the urothelium was found either in vivo or in vitro. There was no difference in the percentage decrease in bladder capacity between cerebral infarction rats pretreated with resiniferatoxin and cerebral infarction rats without pretreatment., Conclusions: Results indicate that expression of sensor molecules in the bladder is altered by distant infarction in the brain. ATP and NGF release from the urothelium also increased. NGF release was related to activation of bladder C-fibers. Bladder C-fibers might not contribute much to decreased bladder capacity caused by cerebral infarction., (© 2016 Wiley Periodicals, Inc.)

Background and Purpose: Two distinct α1 -adrenoceptor phenotypes (α1A and α1L ) have recently been demonstrated to originate from a single α1A -adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1 -adrenoceptors., Experimental Approach: A series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α1A - and α1L -adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca(2+) responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery., Key Results: All the drugs were potent agonists of the α1A -adrenoceptor compared with the α1L -adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an α1A -specific partial agonist that produced partial contractions through α1A -adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α1A - and α1L -adrenoceptors, but was less selective than noradrenaline for α1A -adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery., Conclusions and Implications: The α1A - and α1L -adrenoceptor phenotypes and LUT α1 -adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L -adrenoceptors, the development of α1L -selective agonists may provide clinically useful drugs for SUI therapy., (© 2013 The British Pharmacological Society.)

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Antichollnergic agents are anticipated to diminish storage symptoms, as well as nocturia. Nevertheless, the effect of this treatment on polyuria related to nocturia is not clear. By subgroup analysis of the data set from a phase III clinical trial of antimuscarinic agent for OAB patients in Japan, imidafenacin was found to improve nocturia with a reduction in nocturnal polyuria. This study adds the effects and underlying mechanism of antimuscarinic agents decreasing urine production through inhibition of C-fibre in the bladder of water-leaded rats., Objective: To evaluate the effects and underlying mechanisms of antimuscarinic agents used to decrease in urine production in water-loaded rats., Subjects and Methods: Urine production was measured using a cystostomy catheter in female Sprague-Dawley rats every 2 h. The effect of the antimuscarinic agents atropine, tolterodine and imidafenacin on urine production was investigated under water-loaded conditions, which were induced by i.p. injection of 15 mL saline. Blood samples were collected to determine the levels of antidiuretic hormone (ADH), aldosterone (ALD), atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) before, and 2 and 8 h after, antimuscarinic agent administration. To induce desensitization of C-fibre afferent nerves, resiniferatoxin (RTX)was injected s.c. or intravesically 2 days before experiments., Results: Urine production increased and reached its maximum 2 h after 15 mL saline injection. Imidafenacin and tolterodine decreased urine production in water-loaded rats, but ADH, ALD, ANP and BNP levels were not different between imidafenacin-treated and vehicle-treated rats. The inhibitory effect on urine production was not found in RTX-treated rats. Atropine did not reduce urine production., Conclusion: These results suggest that antimuscarinic agents decrease urine volume through C-fibres in the bladder; thus, antimuscarinics with inhibitory effects on C-fibres could be beneficial for nocturia with nocturnal polyuria., (© 2013 BJU International.)

Purpose: We previously reported that cyclooxygenase inhibitors improved storage function in rats with detrusor overactivity caused by cerebral infarction via C-fiber suppression but the precise mechanism underlying this effect remained unclear. In this study we investigated the effects of cyclooxygenase inhibitors on stretch evoked adenosine triphosphate and prostaglandin E(2) release from bladder epithelium., Materials and Methods: Whole bladders excised from normal rats were fixed vertically in an organ bath filled with Krebs solution. Bladders were infused with 0.3 ml Krebs solution (baseline), followed by 0.9 ml vehicle or 1.5 ml vehicle/drug solution, or 0.3 ml protamine sulfate (Wako Pure Chemical Industries, Osaka, Japan), followed by 0.3 ml prostaglandin E(2) (Nacalai Tesque, Kyoto, Japan). Solutions were allowed to stand for 10 minutes and collected. Adenosine triphosphate and prostaglandin E(2) concentrations were measured by luciferin-luciferase assay and enzyme-linked immunoassay, respectively., Results: Adenosine triphosphate and prostaglandin E(2) release from bladder epithelium was increased by distention in volume dependent fashion. A 100 μM dose of the nonselective cyclooxygenase inhibitors FYO-750, ketoprofen and indomethacin significantly suppressed the increased adenosine triphosphate and prostaglandin E(2) release. Inhibition of adenosine triphosphate release by 100 μM FYO-750 and indomethacin was antagonized by prostaglandin E(2) co-injection. Prostaglandin E(2) increased adenosine triphosphate release in a nondistending condition, and the 1 μM of the selective EP1 and EP3 receptor antagonists ONO-8711 and ONO-AE5-599, respectively, significantly suppressed the increased adenosine triphosphate release., Conclusions: Results indicate that cyclooxygenase inhibitors suppress adenosine triphosphate release from bladder epithelium via decreasing prostaglandin E(2). EP1 and/or EP3 receptors appear to participate in this effect., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: In the present study, we used animal models to investigate whether the selective α(1A)-blocker silodosin exerts inhibitory effects on detrusor overactivity by modulating C-fiber afferent activity., Methods: To desensitize C-fiber afferents, 0.3 mg/kg of resiniferatoxin (RTX) was subcutaneously injected into some female Sprague-Dawley rats 2 days before creation of each model. (1) Left middle cerebral artery occlusion was performed to create a cerebral infarction (CI) model (CI rats). The effects of intravenous (i.v.) and intrathecal (i.t.) administrations of silodosin on cystometrography parameters were evaluated in conscious rats. (2) Rhythmic bladder pressure was recorded in rats under urethane anesthesia. Prostaglandin (PG) E(2) (0.4 mg/mL) was continuously administered intraurethrally, and the effects of intra-arterial (i.a.) silodosin on the micturition reflex (MR) were investigated., Results: (1) Silodosin (i.v.) dose-dependently increased bladder capacity (BC) in CI rats without decreasing bladder contraction pressure, but had no effects on BC in RTX-CI rats. Silodosin (i.t.) markedly increased BC in CI rats, but not in RTX-CI rats. (2) After intraurethral administration of PGE(2), the bladder contraction interval (BCI) was markedly reduced in non-RTX rats, but unchanged in RTX rats. Silodosin (i.a.) significantly prolonged BCI in non-RTX rats receiving intraurethral PGE(2)., Conclusions: These results suggest that the α(1A)-AR subtype activates C-fiber afferents, and that consequently α(1A)-blockade can improve bladder storage function.

Purpose: Impaired melatonin production is involved in disruption of the normal circadian pattern of sleep, which leads to nocturia in older adults. Melatonin improves nocturia. We hypothesized that melatonin could alleviate urinary frequency by suppressing the brain micturition center. We investigated the central contribution of melatonin to bladder function and urine volume., Materials and Methods: Cystometry was done in conscious female Sprague-Dawley rats (Japan SLC, Hamamatsu, Japan). We examined the effect of melatonin alone (4.3 x 10(-1) to 4.3 x 10 pmol intracerebroventricularly) or with the gamma-aminobutyric acid(A) antagonist bicuculline (5.0 x 10(-5) mg/kg intravenously) on bladder function. The influence of melatonin (4.3 x 10 pmol intracerebroventricularly) on urine volume was investigated in water loaded rats. Blood samples were collected to determine antidiuretic hormone, atrial natriuretic peptide and brain natriuretic peptide 4 hours after melatonin administration., Results: Melatonin significantly increased bladder capacity dose dependently by 27.0%, 40.8% and 63.5% at 4.3 x 10(-1), 4.3 and 4.3 x 10 pmol, respectively, but had no significant effect on bladder contraction pressure. Bicuculline inhibited the melatonin induced increases in bladder capacity. Melatonin decreased urine volume in water loaded rats but plasma antidiuretic hormone, atrial natriuretic peptide and bladder contraction pressure were not changed., Conclusions: Results suggest that melatonin increases bladder capacity via gamma-aminobutyric acid(A) receptor in the brain and decreases urine volume. Thus, melatonin could be beneficial for nocturia via a central nervous system effect., (Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: To clarify the effects of zolpidem, a gamma-aminobutyric acid (GABA)(A) receptor agonist, on bladder function, and urine production, we investigated the effects of zolpidem administration on bladder overactivity induced by cerebral infarction (CI) and on urine excretion increased by water overloading in Wistar rats., Methods: CI was induced by left middle cerebral artery occlusion. The effects on bladder function of zolpidem alone or in combination with the GABA(A) receptor antagonist bicuculline, were then examined in the CI rats using cystometry. The antidiuretic effect of zolpidem was investigated in water-loaded and Brattleboro rats (genetically vasopressin-deficient). Blood samples were collected from water-loaded rats to determine the aldosterone level 1 and 6 hr after zolpidem administration., Results: Zolpidem increased bladder capacity dose-dependently, but had no significant effect on bladder contraction pressure in CI rats. Bicuculline dose-dependently inhibited zolpidem-induced increases in bladder capacity without affecting bladder contraction pressure. Zolpidem dose-dependently decreased the volume of urine excreted in water-loaded and Brattleboro rats. Compared with the control group, zolpidem significantly increased the aldosterone concentration in the plasma of water-loaded rats 1 hr after administration., Conclusions: Zolpidem increased bladder capacity via a GABAergic mechanism in CI rats, and suppressed urine excretion via a pathway that was not through activation of vasopressin V(2) receptors in water-loaded and Brattleboro rats. These results suggest that zolpidem may improve nocturia via an increase in bladder capacity and a decrease in urine excretion., ((c) 2009 Wiley-Liss, Inc.)

Aims: Suprapontine lesions, such as those resulting from cerebrovascular disease, cause bladder storage dysfunction. Detrusor overactivity (DO) following cerebral infarction may be explained by impairment of the suprapontine regulatory system. However, precise mechanisms underlying DO is not clear. The following studies were undertaken to examine pharmacological and genetic mechanisms of DO in rats., Results and Conclusions: Mechanisms of long-lasting DO in rats with cerebral infarction require signal transfer, which begins with the opening of glutamate receptors at the dorsal pontine tegmentum. DO induced by cerebral infarction has been proven to be accompanied by an increase in c-fos and zif268 expression in the dorsal pontine tegmentum and periaqueductal gray and mediated by the activation of N-methyl-D-aspartate (NMDA) receptors, cyclooxygenase-2 (COX-2), and prostaglandin E synthase (PGES). Therefore, the arachidonic acid cascade is dynamically activated in the brain after brain ischemia. Bladder sensory pathways are potential targets for drugs used to treat various bladder dysfunctions because of their role in storage symptoms (i.e., urgency, frequency) and in triggering reflex bladder activity. Antimuscarinic drugs and alpha(1)-blockers are the main treatments for overactive bladder, a condition caused by neurologic lesions, aging, bladder outlet obstruction, and other pathologies. These drugs affect sensory bladder storage symptoms, suggesting an action on bladder and urethral afferent pathways. Using animal models of DO, we demonstrated that these drugs improved bladder storage function via suppression of C-fiber afferent nerves from the lower urinary tract.

Objective: To investigate the influence of the mucosa on the inhibitory effects of the ATP-sensitive potassium channel (K(ATP) channel) opener, cromakalim, on the spontaneous contractions of pig bladder strips from the bladder dome and trigone. Little is known about the influence of the mucosa on spontaneous contractions and whether the nature of these contractions differs between the bladder dome and trigone., Materials and Methods: Paired longitudinal strips of female pig bladders were isolated from the dome and trigone. The mucosa was removed from one strip per pair and tissues were set up in organ baths. Spontaneous activity was allowed to develop and recorded, and then cumulative concentration-response curves to cromakalim were obtained. The time needed for spontaneous contractions to develop, the frequency and amplitude of spontaneous contractions, and the effect of cromakalim were analysed. The strips of mucosa removed from the dome to produce denuded strips were also analysed by immunofluorescence using antibodies specific for vimentin and alpha-smooth muscle actin (alpha-SMA)., Results: In the dome removal of the mucosa delayed the development of spontaneous contractions compared with mucosa-intact strips, whilst the trigone strips developed spontaneous contractions soon after set up in the organ baths irrespective of the presence or absence of mucosa. In the dome, cromakalim was more potent in suppressing spontaneous contractions when the mucosa was absent; whilst in the trigone the effects of cromakalim were similar in mucosa-intact and denuded strips. Upon examination of the strips of mucosa by immunofluorescence these strips were shown to contain cells positive for alpha-SMA or vimentin and cells positive for both, suggesting the presence of not only urothelium but also suburothelium and some detrusor smooth muscle bundles., Conclusion: In the dome, the urothelium and suburothelium reduce the inhibitory effect of cromakalim on spontaneous contractions, whilst in the trigone these structures appear to have little influence. The mechanism for generating spontaneous contractions in the intact strips seems to be linked to the urothelium and suburothelium in the dome but not in the trigone.

Objectives: Although invasive and expensive, the pressure-flow study is known as the reference standard for the diagnosis of bladder outlet obstruction. We investigated the usefulness of ultrasound-estimated bladder weight (UEBW) as a predictor of the need for surgery for benign prostatic hyperplasia (BPH)., Methods: A total of 97 consecutive male patients >50 years old with lower urinary tract symptoms (LUTS) were prospectively enrolled in this study. The surgery rate was correlated with the UEBW, the results of uroflowmetry, the postvoid residual urine volume, prostate volume, and International Prostate Symptom Score., Results: Surgery for BPH was performed in 37 of the 97 patients studied. The surgery rate was associated with a high UEBW (>or=35 g), severe LUTS (International Prostate Symptom Score of >or=20), a voided volume of <100 mL at free uroflowmetry, and poor uroflow (maximal flow rate of <10 mL/s). Multivariate analysis revealed that severe LUTS and a high UEBW were the risk factors for surgery for BPH., Conclusions: The results of our study have shown that the UEBW can be regarded as a useful parameter to identify patients with LUTS who are at risk of needing surgery for BPH.

Increase in bladder mucosal permeability can be reproduced by intravesical administration of protamine sulfate (PS); however, the influence of PS once administered into the bladder disappears within several days. We developed a chronic animal model of urothelial injury using PS. Insertion of a polyethylene catheter through the bladder dome was performed in female Wistar rats. The other end of the catheter was connected to an osmotic pump for continuous delivery of PS or vehicle for 2 wk. Urinary frequency (UF) and voided volume (VV) were measured in the metabolic cage. The fifth group of rats received a high dose of PS (10 mg/ml) for 2 wk and were followed for a further 2 wk without PS. The sixth group received a high dose of PS for 2 wk and loxoprofen (0.1 mg.kg(-1).day(-1)) for 4 wk. UF was increased, and VV was reduced in rats treated with a high dose of PS but not changed in rats treated with a vehicle or a low dose of PS (1 mg/ml). UF was further increased in the fifth group, while unchanged in the sixth group. Histological sections in rats treated with a high dose of PS demonstrated a loss of the upper layer of urothelial cells and an increased number of mast cells. PGE2 level in the bladder was significantly elevated in the fifth group. These results indicate that chronic urotherial injury leads to an increase in UF and a decrease in VV. Increased PGE2 level in the bladder is likely to be associated with long-lasting storage dysfunction.

Muscarinic receptors in the human and rat lower urinary tract (urinary bladder detrusor muscle and mucosa, and prostate) were identified by intact tissue segment binding assays with two radioligands, and the effects of prolonged receptor activation in vitro on muscarinic receptors were examined. Hydrophilic [(3)H]-NMS and hydrophobic [(3)H]-QNB bound to the detrusor muscle segments with the same density, suggesting that the muscarinic receptors were localized at the plasma membrane. While the density of muscarinic receptor was higher in detrusor muscle than in the bladder mucosa and prostate, there was no species-specific difference either in density or in subtype distribution (M(1), M(2), and M(3) subtypes in detrusor; M(2) and M(3) subtypes in bladder mucosa; and M(1) and M(2) subtypes in prostate). Incubation of detrusor strips with carbachol decreased [(3)H]-NMS binding sites within 20 min, followed by a reduction of [(3)H]-QNB binding sites after a 60-min lag phase. The loss of the binding sites over 3 h after carbachol treatment was the same (approximately 40%) for both radioligands. The present intact tissue segment binding assay reveals tissue-specific and plasma membrane distribution of distinct muscarinic receptor subtypes and their dynamic changes (internalization and down-regulation) in lower urinary tract of humans and rats.

Overactive bladder (OAB), according to the International Continence Society (ICS) definition, is a symptom syndrome, with urgency as the cornerstone symptom. However, the word 'urgency' and its definition continue to be the subject of much debate and confusion. It is generally difficult for patients to differentiate urgency from normal urge, particularly when the desire to void is strong. To investigate the micturition behavior associated with OAB, we conducted a Patient Trust Study in 21 intelligent (i.e., to be 'trusted') female patients who could clearly and accurately discriminate between urgency and urge. The results showed that in 43% of patients seeking medical care, urgency episodes occurred less than once/day, and some patients had days without urgency. Our patients deferred voiding until bladder sensation was relatively strong, suggesting that coping was not common among these patients. Four of the 21 patients studied experienced spontaneous resolution of several urgency episodes. At volumes exceeding 40% of the maximum bladder volume (MBV), urgency episodes occurred frequently and independently of the bladder volume, indicating that 40% of the MBV may be a threshold of bladder volume to induce urgency. A linear relationship was observed between bladder volume and increasing bladder sensation. However, compared with normal subjects, urge sensation increased markedly at any given bladder volume among patients with OAB in our study. This hypersensitivity was observed in our patients regardless of urgency episodes. We therefore hypothesized that OAB may be more accurately defined as a hypersensitivity disorder rather than a syndrome characterized by urgency., ((c) 2007 Wiley-Liss, Inc.)

Purpose: Alpha(1)-blockers improve voiding symptoms by decreasing prostatic and urethral smooth muscle tone. However, to our knowledge the mechanism underlying improvements in storage symptoms is not known. Topical application of prostaglandin E(2) to the rat lower urinary tract stimulates the micturition reflex. Using an animal model we investigated whether the alpha(1)-blocker tamsulosin (Astellas Pharma, Tokyo, Japan) acts on C-fiber afferent activity and, if so, the location of this effect., Materials and Methods: To induce desensitization of C-fiber afferent activity resiniferatoxin (0.3 mg/kg) was subcutaneously injected in female Sprague-Dawley rats 2 days before experiments. Simultaneous recordings of urethral pressure and rhythmic bladder pressure were made with the rats under urethane anesthesia. Prostaglandin E(2) (0.4 mg/ml) was continuously administered intravesically or intraurethrally to rats pretreated with resiniferatoxin (resiniferatoxin rats) or rats without pretreatment (nonresiniferatoxin rats). We investigated the effects on the micturition reflex of intravenous (2.2 x 10(-1) to 2.2 x 10(3) nM/kg) or intrathecal (0.001 to 0.1 nmol) administration of tamsulosin., Results: The bladder contraction interval was markedly decreased after intravesical or intraurethral administration of prostaglandin E(2) in nonresiniferatoxin rats but it was unchanged in resiniferatoxin rats. This effect was antagonized by the EP1 receptor antagonist ONO-8711 (6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid). Intravenous administration of tamsulosin significantly increased the bladder contraction interval in nonresiniferatoxin rats receiving intraurethral prostaglandin E(2) but it had no effect on nonresiniferatoxin rats receiving intravesical prostaglandin E(2). Intrathecal administration of tamsulosin produced a slight and insignificant increase in the bladder contraction interval in nonresiniferatoxin rats receiving intraurethral prostaglandin E(2)., Conclusions: These results suggest that prostaglandin E(2) enhances the micturition reflex through C-fiber afferents and tamsulosin had an inhibitory effect on the C-fiber urethral afferent nerves, thereby improving bladder storage function.

Aims: Alpha1-blockers improve voiding symptoms through the reduction of prostatic and urethral smooth muscle tone; however, the underlying mechanism of improvement of storage symptoms is not known. Using a rat model of detrusor overactivity caused by cerebral infarction (CI), we undertook the present study to determine whether the effect of an alpha1-blocker, naftopidil, is dependent on the suppression of C-fiber afferents., Methods: To induce desensitization of C-fiber bladder afferents, we injected resiniferatoxin (0.3 mg/kg, RTX) sub-cutaneously to female Sprague-Dawley rats 2 days prior to left middle cerebral artery occlusion (MCAO) (RTX-CI rats). As controls we used rats without RTX treatment (CI rats). MCAO and insertion of a polyethylene catheter through the bladder dome were performed under halothane anesthesia. We investigated the effects on cystometrography (CMG) of intravenous (i.v.), intracerebroventricular (i.c.v.), or intrathecal (i.t.) administration of naftopidil in conscious CI rats., Results: Bladder capacity (BC) was markedly reduced after MCAO in both RTX-CI and CI rats. I.v. administration of naftopidil significantly increased BC in CI rats without an increase in residual volume, but it had no effects on BC in RTX-CI rats. I.t. administration of naftopidil significantly increased BC in CI but not in RTX-CI rats., Conclusions: These results suggest that naftopidil has an inhibitory effect on C-fiber afferents in the lumbosacral spinal cord, improving BC during the storage phase.

Purpose: We determined whether the effects of antimuscarinics depend on the suppression of C-fiber bladder afferent nerves. We administered tolterodine intravenously or intravesically., Materials and Methods: To induce C-fiber bladder afferent nerve desensitization resiniferatoxin (RTX) (0.3 mg/kg) was injected subcutaneously in female Sprague-Dawley rats 2 days prior to left middle cerebral artery occlusion (MCAO). As controls, we used rats treated with ethanol and saline vehicle (VEH). Insertion of a polyethylene catheter through the bladder dome and MCAO were performed using halothane anesthesia. The effects of intravenous (0.2 to 2000 nM/kg) or intravesical (0.2 or 2 nM) tolterodine, an antimuscarinic agent, on cystometrography were investigated in conscious rats with a cerebral infarct (CI). Tolterodine was instilled intravesically for 30 minutes and cystometry was repeated., Results: Bladder capacity (BC) was markedly decreased after MCAO in RTX treated (RTX-CI) and VEH treated (VEH-CI) rats. Low tolterodine doses (0.2 or 2 nM/kg) significantly increased BC in VEH-CI rats without increasing residual volume but it had no effects on BC in RTX-CI rats. At the highest dose (2,000 nM/kg) the drug significantly decreased bladder contraction pressure and increased residual volume in RTX-CI and VEH-CI rats. Intravesical administration of tolterodine (0.2 or 2 nM) significantly increased BC in VEH-CI rats. However, tolterodine had no effect on BC in RTX-CI rats., Conclusions: These results suggest that at low doses tolterodine exerts an inhibitory effect on C-fiber bladder afferent nerves, thereby, improving BC during the storage phase.

Purpose: It has been reported that the opiate receptor system in the spinal cord is involved in bladder and urethral function. We determined whether U-50488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide), a kappa opioid receptor agonist, could decrease detrusor-sphincter dyssynergia (DSD) and, thus, improve voiding efficiency in conscious, spinal cord injured (SCI) rats., Materials and Methods: Experiments were done in female Sprague-Dawley rats in which the spinal cord was completely transected at the T6-8 level 4 weeks prior to performing cystometry while conscious and held in a restraining cage. Experiments were also performed in normal spinal cord rats. Saline was infused (0.1 ml per minute) via the cystostomy catheter into the bladder. Voiding efficiency was determined by measuring voided and residual volumes. After performing a control cystometrogram increasing doses of U-50488 (0.01, 0.1, 1 and 10 mg/kg) were administered intravenously at 1-hour intervals. The effects of nor-binaltorphimine dihydrochloride, a kappa opioid receptor antagonist, on U-50488 induced changes in voiding parameters were also examined., Results: A high dose of U-50488 (1 to 10 mg/kg) significantly decreased contraction amplitude and bladder capacity (p <0.01 to 0.05) in normal spinal cord and SCI rats. A low dose of U-50488 (0.01 mg/kg) increased voiding efficiency by 32.7% without decreasing bladder capacity in SCI rats. Nor-binaltorphimine hydroparameters counteracted the effect of U-50488 induced changes., Conclusions: These results suggest that the kappa opioid receptor system is related to DSD caused by spinal cord injury. The kappa opioid receptor agent is believed to have therapeutic potential for treating DSD associated with SCI.

Purpose: The maintenance of long lasting bladder overactivity caused by cerebral infarction is believed to require transcription in the pontine micturition center. Therefore, we examined the influence of the RNA synthesis inhibitor actinomycin D (Banyu Pharmaceutical Co., Ltd., Tokyo, Japan) on bladder overactivity induced by left middle cerebral artery occlusion., Materials and Methods: Rats under halothane anesthesia were injected with actinomycin D or vehicle (mannitol) into the bilateral dorsal pontine tegmentum, followed by middle cerebral artery occlusion. Awake rats were cystometrically examined for 12 hours. The expression of c-fos and zif268 mRNA in the dorsal pontine tegmentum was monitored with real-time polymerase chain reaction., Results: Injection of actinomycin D produced a significant decrease in bladder capacity in sham operated rats but bladder capacity returned to control levels before sham operation within 6 hours. In cerebral infarcted rats pretreated with vehicle bladder capacity was significantly decreased after middle cerebral artery occlusion and it remained consistently below half of pre-occlusion capacity. Actinomycin D blocked the decrease in bladder capacity in cerebral infarcted rats. In actinomycin D treated cerebral infarcted rats bladder capacity gradually recovered and returned to the control level before middle cerebral artery occlusion within 10 hours. Actinomycin D suppressed an increase in c-fos mRNA expression 1 hour after middle cerebral artery occlusion as well as in zif268 3 hours after occlusion. Administering actinomycin D 0.5 or 1 hour after middle cerebral artery occlusion also suppressed bladder overactivity until at least 10 hours after occlusion but injection 3 hours after occlusion did not., Conclusions: These results indicate that an RNA synthesis inhibitor can prevent a late stage of bladder overactivity. Transcription in the dorsal pontine tegmentum was found to be necessary to maintain the long lasting bladder overactivity caused by cerebral infarction.

Purpose: We investigated the contribution of cerebral nitric oxide to neurogenic voiding dysfunction after cerebral infarction., Materials and Methods: The left mid cerebral artery in female Sprague-Dawley rats was occluded with 4-zero monofilament nylon thread. Bladder activity was monitored during infusion cystometrography. Time or dose dependent effects of intracerebral ventricular administration of the nonselective nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), were investigated in conscious, sham operated and cerebral infarcted rats. The selective neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl) imidazole was also administered to determine the participation of nitric oxide synthase subtypes. Cross-sectional infarct area was measured and infarct volume was calculated 12 hours after mid cerebral artery occlusion., Results: Bladder capacity was reduced by 54% 30 minutes after mid cerebral artery occlusion. L-NAME significantly increased bladder capacity in a dose and time dependent manner in cerebral infarcted rats but had no effect on sham operated rats. L-NAME (50 microg./kg.) administered 3 or 5 hours after occlusion significantly increased bladder capacity. This effect of L-NAME was reversed by injecting 250 microg. L-arginine per rat, which alone did not produce any significant change in bladder capacity in cerebral infarcted rats. Administration of 1-(2-trifluoromethylphenyl) imidazole also significantly increased bladder capacity in these rats. On the other hand, 5 microg. of the nitric oxide donor FK-409 per rat reduced bladder capacity for 10 to 15 minutes. None of the drugs affected infarct volume., Conclusions: These results indicate that supraspinal nitric oxide has an important role in bladder overactivity after cerebral infarction but it does not affect normal micturition in rats. This finding suggests a central mechanism sensitive to nitric oxide for bladder overactivity after cerebral infarction.

Objectives: To elucidate the mechanism of action of the α1‐blocker, naftopidil, in partial bladder outlet obstruction animals, by studying non‐voiding contractions, and the levels of mediators were measured with resiniferatoxin treatment. Methods: A total of 35 female Wistar rats were randomly divided into a sham or bladder outlet obstruction group, and rats in each group were given vehicle or resiniferatoxin. Incomplete urethral ligation was applied to the bladder outlet obstruction group. After cystometry, the intravesical level of prostaglandin E2 and adenosine 5′‐triphosphate was measured in the instilled perfusate collected. Naftopidil was given at the time of cystometry. Results: In bladder outlet obstruction rats, non‐voiding contractions, bladder capacity, and the intravesical levels of prostaglandin E2 and adenosine 5′‐triphosphate were markedly increased compared with sham rats. Naftopidil decreased non‐voiding contractions, enlarged the bladder capacity, and decreased the intravesical levels of prostaglandin E2 and adenosine 5′‐triphosphate. Resiniferatoxin enhanced non‐voiding contractions. The effects of naftopidil on non‐voiding contractions and the intravesical level of prostaglandin E2, but not adenosine 5′‐triphosphate, were tolerant to resiniferatoxin. Conclusions: In bladder outlet obstruction rats, one cause of generation of non‐voiding contractions might be bladder wall distension, but not transient receptor potential cation channel V1. The increase in intravesical prostaglandin E2 might also be associated with the generation of non‐voiding contractions. Naftopidil inhibits the increase in non‐voiding contractions and decreases the intravesical level of prostaglandin E2, which are independent of transient receptor potential cation channel V1. [ABSTRACT FROM AUTHOR]

Purpose The objective of this multicenter cross-sectional study was to investigate the relationship of nocturnal polyuria in patients with common lifestyle related diseases and overactive bladder, with special attention to hypertension. Materials and Methods After baseline assessment, patients recorded 24-hour urinary frequency/volume, blood pressure and heart rate for 3 days. They were stratified into 4 groups based on mean blood pressure, including no hypertension, and controllable, untreated and uncontrolled hypertension, respectively. Results The 2,353 eligible patients, who had urinary urgency once or more per week and 1 or more nocturnal toilet visits, were enrolled from 543 sites in Japan. Of these patients complete data, including the 24-hour frequency volume chart, were collected from 1,271. Multivariable analyses showed a statistically significant association of nocturnal polyuria with increasing age (OR 1.04, 95% CI 1.02–1.05, p <0.001) and gender (women vs men OR 0.75, 95% CI 0.59–0.96, p = 0.02), and for controllable (OR 1.10, 95% CI 0.83–1.460), untreated (OR 2.62, 95% CI 1.55–4.45) and uncontrolled (OR 1.15, 95% CI 0.81–1.62) hypertension vs no hypertension (p = 0.005). However, when assessed separately in men and women, hypertension and heart rate were significantly associated with nocturnal polyuria in women alone (p = 0.01 and 0.03, respectively). Lower urinary tract symptoms suggestive of benign prostatic hyperplasia were significantly associated with nocturnal polyuria in men alone (p <0.001). Conclusions The current study demonstrates that nocturnal polyuria was significantly associated with age, male gender, and untreated hypertension in patients with lifestyle related diseases and overactive bladder. The association between hypertension and nocturnal polyuria was significant in women alone. [ABSTRACT FROM AUTHOR]

Purpose: We compared changes in nocturia and sleep related parameters between the anticholinergic solifenacin and placebo in patients with overactive bladder associated with nocturia. Materials and Methods: We performed subgroup analysis of data from a randomized, controlled trial of solifenacin (5 or 10 mg) in Japan. Men and women 20 years old or older with overactive bladder were eligible for study participation. Patients who voided at least once during the night at baseline and who completed efficacy and quality of life assessment at baseline and 12 weeks (treatment end) were included in analysis. We compared placebo with the posttreatment change in nocturia and daytime frequency, volume voided per micturition, sleeping time, hours of undisturbed sleep and sleep related quality of life. Results: Subgroup analysis included 962 patients. Solifenacin 10 mg significantly decreased nocturia episodes by 0.46 episodes (p = 0.0449). Solifenacin 5 and 10 mg significantly increased nighttime volume voided per micturition by 30 and 41 ml (p = 0.0033 and <0.0001, respectively). Compared with placebo (33 minutes) the hours of undisturbed sleep significantly increased by 59 and 60 minutes (p = 0.0196 and 0.0195) in patients with solifenacin 5 and 10 mg, respectively. Significant improvement was observed in sleep related quality of life for solifenacin 5 and 10 mg (each p <0.001). Results must be interpreted with caution due to the exploratory nature of this analysis. Conclusions: Solifenacin 10 mg decreases nocturia episodes. Solifenacin 5 and 10 mg increases nighttime volume voided per micturition and may improve quality of sleep and sleep related quality of life in patients with overactive bladder. [ABSTRACT FROM AUTHOR]

Purpose: We previously reported that cyclooxygenase inhibitors improved storage function in rats with detrusor overactivity caused by cerebral infarction via C-fiber suppression but the precise mechanism underlying this effect remained unclear. In this study we investigated the effects of cyclooxygenase inhibitors on stretch evoked adenosine triphosphate and prostaglandin E2 release from bladder epithelium. Materials and Methods: Whole bladders excised from normal rats were fixed vertically in an organ bath filled with Krebs solution. Bladders were infused with 0.3 ml Krebs solution (baseline), followed by 0.9 ml vehicle or 1.5 ml vehicle/drug solution, or 0.3 ml protamine sulfate (Wako Pure Chemical Industries, Osaka, Japan), followed by 0.3 ml prostaglandin E2 (Nacalai Tesque, Kyoto, Japan). Solutions were allowed to stand for 10 minutes and collected. Adenosine triphosphate and prostaglandin E2 concentrations were measured by luciferin-luciferase assay and enzyme-linked immunoassay, respectively. Results: Adenosine triphosphate and prostaglandin E2 release from bladder epithelium was increased by distention in volume dependent fashion. A 100 μM dose of the nonselective cyclooxygenase inhibitors FYO-750, ketoprofen and indomethacin significantly suppressed the increased adenosine triphosphate and prostaglandin E2 release. Inhibition of adenosine triphosphate release by 100 μM FYO-750 and indomethacin was antagonized by prostaglandin E2 co-injection. Prostaglandin E2 increased adenosine triphosphate release in a nondistending condition, and the 1 μM of the selective EP1 and EP3 receptor antagonists ONO-8711 and ONO-AE5-599, respectively, significantly suppressed the increased adenosine triphosphate release. Conclusions: Results indicate that cyclooxygenase inhibitors suppress adenosine triphosphate release from bladder epithelium via decreasing prostaglandin E2. EP1 and/or EP3 receptors appear to participate in this effect. [Copyright &y& Elsevier]

Purpose: Cyclooxygenase inhibitors decrease micturition frequency in animals with bladder inflammation but to our knowledge the influence of cyclooxygenase inhibitors on detrusor overactivity has not been investigated. We evaluated the effects, and the site and mechanism of action of cyclooxygenase inhibitors on detrusor overactivity induced by cerebral infarction. Materials and Methods: Cerebral infarcted rats underwent cumulative intravenous administration of the selective cyclooxygenase-1 inhibitor SC-560 (Sigma®), the selective cyclooxygenase-2 inhibitor rofecoxib (Kemprotec, Middlesbrough, United Kingdom) or the nonselective cyclooxygenase inhibitor FYO-750 hourly plus a single intravenous administration of SC-560, rofecoxib or SC-560 plus rofecoxib. To evaluate the site of action cerebral infarcted rats underwent single intracerebroventricular or intrathecal administration of FYO-750. To evaluate the mechanism of action FYO-750 was intravenously administered in diuretic rats or cerebral infarcted rats pretreated with resiniferatoxin. Results: For cumulative administration SC-560 (0.3 mg/kg), rofecoxib (0.3 mg/kg) and FYO-750 (0.1 to 1 mg/kg) significantly increased bladder capacity. For single administration neither SC-560 (0.03 mg/kg) nor rofecoxib (0.03 mg/kg) affected bladder capacity but SC-560 plus rofecoxib significantly increased bladder capacity vs vehicle. Intracerebroventricular and intrathecal administration of FYO-750 did not affect bladder capacity. FYO-750 did not affect urinary production in diuretic rats and the effects of FYO-750 were blocked by resiniferatoxin except at the highest drug dose. Conclusions: Results indicate that cyclooxygenase inhibitors improve detrusor overactivity caused by cerebral infarction by suppressing peripheral C fiber''s without affecting urinary production. The nonselective cyclooxygenase inhibitor showed more potent efficiency than the selective cyclooxygenase-1 or the cyclooxygenase-2 inhibitor alone. [Copyright &y& Elsevier]

Previous reports have shown that N-methyl-d-aspartate (NMDA) glutamatergic and D2 dopaminergic mechanisms have independent excitatory effects on bladder activity in normal and cerebral infarcted (CI) rats under urethane anesthesia. The study presented here was undertaken to investigate the interaction between these two mechanisms on bladder activity in conscious Sprague–Dawley female rats with or without cerebral infarction. Occlusion of the left middle cerebral artery or a sham operation (SO) was performed under halothane anesthesia. After recovery from the anesthesia, bladder activity was monitored continuously by means of infusion cystometrography in awake rats. The effects of cumulative intravenous doses of quinpirole (0.001–1 mg/kg), a D2 dopamine receptor agonist, were studied in awake SO and CI rats with or without dizocilpine (10 mg/kg) pretreatment. The effects of dizocilpine (1 or 10 mg/kg) were also examined in other SO or CI rats pretreated with 1 mg/kg of quinpirole. Bladder capacity in CI rats was significantly smaller (0.18 ml) than that in SO rats (0.48 ml). Quinpirole (0.1 and 1 mg/kg) further reduced bladder capacity in both types of rats, an effect blocked by sulpiride (20 mg/kg), a D2 dopamine receptor antagonist. The effect of quinpirole was also antagonized by dizocilpine (1 mg/kg) to a significantly (P < 0.01) greater degree in CI than in SO rats. In SO rats pretreated with 1 mg/kg of quinpirole, dizocilpine significantly increased bladder capacity in a dose-dependent manner. After the maximum dose (10 mg/kg) of dizocilpine, sulpiride did not produce any changes in bladder activity. In CI rats pretreated with 1 mg/kg of quinpirole, 1 mg/kg of dizocilpine increased bladder capacity. After administration of the maximum dose of dizocilpine (10 mg/kg), which did not produce an additional effect, sulpiride (20 mg/kg) increased bladder capacity by 58.3%. These results indicate that in awake rats D2 dopaminergic excitatory effects on the urinary bladder are mediated in part by NMDA glutamatergic mechanisms and in part by non-NMDA mechanisms. The latter type was more prominent in CI rats, indicating that the bladder hyperactivity induced by cerebral infarction may be mediated by an alteration in dopaminergic–glutamatergic interactions in the brain. [Copyright &y& Elsevier]